Background: Urinary catecholamines and metanephrines have been proposed as a diagnostic tool for identifying canine pheochromocytomas, but the effects of critical illness on urine concentrations of catecholamines and metanephrines is currently unknown. Objectives: To examine the effects of illness on urine concentrations of catecholamines and metanephrines in dogs. Animals: Twenty-five critically ill dogs and twenty-five healthy age- and gender-matched control dogs. Methods: Prospective observational study. Urine was collected from healthy and critically ill dogs and urine concentrations of epinephrine, norepinephrine, metanephrine, and normetanephrine were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. Urinary catecholamine and metanephrine:creatinine ratios were calculated and compared between groups. Results: Urinary epinephrine, norepinephrine, metanephrine, and normetanephrine:creatinine ratios were higher in critically ill dogs when compared to a healthy control population (P = 0.0009, P < 0.0001, P < 0.0001, and P < 0.0001 respectively). Conclusions and Clinical Relevance: Illness has a significant impact on urinary catecholamines and their metabolites in dogs. Further investigation of catecholamine and metanephrine concentrations in dogs with pheochromocytomas is warranted to fully evaluate this test as a diagnostic tool, however the findings of this study suggest that the results may be difficult to interpret in dogs with concurrent illness. / Master of Science

This research explores the question of what role medical family therapists play on a health care team when working with serious pediatric illness. Seven participants from three different health care settings were interviewed. Results were organized within the ecological systems framework (Bronfenbrenner, 1979) according to the various ways participants became a part of the family's illness experience. Participants identified roles directly with the family, with the health care team, and within the larger health care system. Clinical implications are identified concerning the preparation of the health care system for the continued growth and evolution of the field of medical family therapy. / Master of Science

This thesis focuses on the relationship between technology and caring in technologically intense environments. The overall aim was to uncover the meaning of care in those environments as experienced by patients and caregivers. Moreover, the study aimed at finding a deeper understanding for the almost total dominance of technology in care in intensive care. The thesis includes three empirical studies and one theoretical, philosophical study. The research was guided by a phenomenological and lifeworld theoretical approach. Research data consist of quantitative parameters and qualitative interviews with caregivers and patients. Data was analysed and synthesised with aim of seeking meaning through openness, sensitivity and a reflective attitude. The goal was to reach the general structure of the phenomenon and its meaning constituents. The result shows that an intensive care unit is a cognitive and emotionally complex environment where caregivers are juggling a precarious handful of cards. Despite being constantly monitored and observed, intensive care patients express that they feel invisible. The patient and the apparatus easily meld into a unit, one item to be regulated and read. From the patients’ perspective, caregivers demonstrate keen vigilance over technological devices and measured parameters, but pay scant attention to their stories and experiences. Technology, with its exciting captive lure and challenging character, seduces the caregivers and lulls them into a fictive sense of security and safety. Technical tasks take precedence or have more urgency than caring behaviour. A malaise settles on caregivers as they strive for garnering the security that technology promises. Yet simultaneously, insecurity creeps in as they read the patient’s biological data. Technical tasks take precedence over and seemingly are more urgent than showing care. Listening, inspiring trust, and promoting confidence no longer have high priority. Trying to communicate ‘through’ technology is so complex, that it is a difficult challenge to keep in perspective what or who is the focus; ‘seeing’ or caring. Technology should be like a catalyst; do its ‘thing’ and withdraw ‘unnoticed’. This thesis has contributed in gaining deeper knowledge about care in technologically intense environments and the impact of technology. The main contribution is that caregivers need to be aware that the roar of technology silences the subtle attempts of the critically ill or injured person to give voice to his or her needs. In conclusion, the challenges for caregivers are to distinguish when to heighten the importance of the objective and measurable dimensions provided by technology and when to reduce their importance. In order to magnify the patients’ lived experiences. It is a question of balancing state-of-the-art technology with integrative and comprehensive care, of harmonizing the demands of subjectivity with objective signs.

A following study on vancomycin demonstrated the differing pharmacokinetics during the course of a septic insult, day 2 pharmacokinetics differing from day 7. / An important study showed that some septic patients with "normal" serum creatinines can have very high creatinine clearances. It follows that drugs which are renally excreted will have high clearances and illustrates why many of the above patients had low serum levels of antibiotic, a reason why some ICU patients require different dosing to ward patients. / Due to the required fluid loading and inotropic use in septic patients, creatinine clearances and drug clearances are often raised. This results in low serum concentrations at the end of a standard dosing interval. / My beta-lactam antibiotic work has repeatedly demonstrated low serum levels at the end of the standard dosing interval. In view of beta-lactam time-dependent kill characteristics we designed a continuous infusion protocol which we validated in a follow-up paper. / The inflammatory response of infections involves endothelial damage and capillary permeability. With associated fluid shifts of severe sepsis and treatment thereof, the volume of distribution (Vd) of antibiotics that distribute into the extracellular space (aminoglycosides, glycopeptides) is high. Peak serum levels for these antibiotics are therefore lower than those found in non-critically ill and in normal volunteers. It is noteworthy that this change in Vd is not apparent with drugs that have good tissue penetration (e.g. ciprofloxacin). / This thesis is a compilation of 11 of my prospectively designed studies plus extracts from 5 published reviews, focusing on pharmacokinetic (PK) aspects of antibiotics in ICU patients, all published in internationally peer-reviewed journals. / Two large PK studies on ciprofloxacin (a drug that has excellent tissue penetration) designed to address possible PK differences over time, could not demonstrate this difference in adults nor in two groups of paediatric patients where differences in body water are significant. / Two papers investigated the pharmacokinetics of amicakin in adult and paediatric patients documenting the benefit of extended interval dosing. / We automatically assume that antibiotic prescribing data, collated from healthy volunteers and not so ill patients, can be transcribed into the Intensive Care Unit. This is not so. / Jeffrey Lipman. / "April 2005." / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1548. / Thesis (M.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 235-254). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Critical illness is an aetiologically and clinically heterogeneous syndrome that is characterised by organ failure and immune dysfunction. Mortality in critically ill patients is driven by inflammation-associated organ damage and a profound vulnerability to nosocomial infection. Both factors are influenced by the complement protein C5a, released by unbridled activation of the complement system during critical illness. C5a suppresses antimicrobial functions of key immune cells, in particular the neutrophil, and this suppression has been shown to be associated with poorer outcomes amongst critically ill adults. The intracellular signalling pathways which mediate C5a-induced neutrophil dysfunction are incompletely understood, and scalable tools with which to assess immune cell dysfunction in patients are lacking. This thesis aimed to develop tools with which to assess neutrophil function and delineate intracellular signalling pathways driving C5a-induced impairment. Neutrophils were isolated from healthy volunteer blood and functions (priming, phagocytosis and reactive oxygen species production) were assessed using light microscopy, confocal microscopy and flow cytometry. A new assay was developed using an Attune Nxt™ acoustic focusing cytometer (Life Technologies) which allowed the rapid assessment of multiple neutrophil functions in small samples of unlysed, minimally-manipulated human whole blood. Complete proteomes and phosphoproteomes of phagocytosing neutrophils were obtained from four healthy donors pre-treated with C5a or vehicle control. Several key insights were gained from this work and are summarised here. Firstly, C5a was found to induce a prolonged (greater than seven hours) impairment of neutrophil phagocytosis. This defect was found to be preventable by previous or concurrent phagocytosis, indicating common signalling mechanisms. Secondly, a novel assay was developed which allows the rapid assessment of multiple neutrophil functions in less than 2 mL of whole blood, and this assay can feasibly be applied in clinical settings. Thirdly, cell-surface expression of the C5a receptor was found to be markedly decreased during phagocytosis, and this decrease was not mediated by protease activity. Finally, unbiased proteomics quantified 4859 proteins and 2712 phosphoproteins respectively. This quantification is the deepest profile of the human neutrophil proteome published to date, and has revealed novel insights into the mechanisms of C5a-induced neutrophil dysfunction and phagocytosis.

Introdução: A polineuromiopatia do doente crítico (PNMDC) é uma freqüente complicação neuromuscular adquirida na Unidade de Terapia Intensiva (UTI). O principal fator de risco está relacionado à sepse e à disfunção de múltiplos órgãos sendo que sua incidência pode variar entre 50 a 100%. A confirmação do diagnóstico é feita pela eletroneuromiografia, porém sugere-se que as características clínicas (fraqueza muscular, alterações sensoriais e de reflexos e dificuldade de desmame da ventilação mecânica) possam ser suficientes para o diagnóstico clínico. Objetivo: Identificar sinais clínicos que possam ser utilizados como marcadores para auxiliar no diagnóstico de PNMDC à beira do leito em pacientes sépticos. Resultados: Cinquenta pacientes foram avaliados e divididos em dois grupos conforme o resultado da eletroneuromiografia (PNMDC e não PNMDC). Os pacientes com PNMDC tinham idade maior e eram mais graves (APACHE IV e SAPS 3), permaneceram maior período hospitalizados e necessitaram de suporte ventilatório por mais tempo. Os pontos de corte: <40 para escore Medical Research Council (MRC); <7 kg para dinamometria em homens e <4 kg em mulheres; <34 cmH2O para pressão expiratória máxima e >-40 cmH2O para pressão inspiratória máxima conseguiram identificar com bons níveis de sensibilidade e de especificidade os pacientes com PNMDC. Conclusões: A força muscular esquelética pelo escore MRC, dinamometria e pressões respiratórias máximas é uma método simples que permite a identificação de PNMDC em uma avaliação clínica à beira do leito. / Introduction: Critical illness polyneuromyopathy (CIPNM) is a frequent acquired neuromuscular complication in the Intensive Care Units (ICU). The main risk factor is related to sepsis and multiple organs dysfunction and the incidence of this disorder can reach 50-100%. The diagnosis is made by electromyography, but it is suggested that the clinical features (muscle weakness, sensory and reflexes changes and difficulty in weaning patients from mechanical ventilation) may be sufficient for clinical diagnosis. Objective: To identify clinical signs that may be used as markers to help in the bedside diagnosis of CIPNM in septic patients. Results: Fifty patients were evaluated and divided into two groups according to the results of electromyography (CIPNM and non-CIPNM). The patients with CIPNM were older, showed more severe illness (Apache IV and Saps 3), remained hospitalized for longer period of time, and required longer period of ventilatory support than non-CIPNM. The cutoffs that could identify the patients with CIPNM with good levels of sensitivity and specificity were: Medical Research Council (MRC) score <40; dynamometry <7 kg for men and <4 kg for women, maximal expiratory pressure (MEP) <34 cmH2O and maximal inspiratory pressure (MIP) > -40 cmH2O . Conclusions: The assessment of skeletal muscle strength by MRC score, dynamometry and maximum respiratory pressure is a simple method that allows the diagnosis of CIPNM through a clinical examination at the bedside.

Physical, psychological, and social debilities are common among survivors of critical illness. Survivors of critical illness require rehabilitative services during recovery in order to return to functional independence, but the structure and access of such services remains unclear. The purpose of this qualitative study was to explore the vital issues affecting quality of life from the perspective of critical illness survivors and to understand these patients' experiences with rehabilitative services in the United States. The theoretical framework guiding this study was Weber's rational choice theory, and a phenomenological study design was employed. The research questions focused on the survivors' experiences with rehabilitative services following critical illness and post-intensive care unit quality of life. Participants were recruited using purposeful sampling. A researcher developed instrument was used to conduct 12 semistructured interviews in central North Carolina. Data from the interviews were coded for thematic analysis. The findings identified that aftercare lacked unity, was limited by disparate information, and overuses informal caregivers. In addition, survivors' recovery depended on being prepared for post-intensive care unit life, access to recovery specific support structures, and the survivors' ability to adapt to a new normalcy. Survivors experienced gratitude for being saved, which empowered them to embrace new life priorities. The implications for social change include improved understanding of urgently needed health care policies to provide essential therapies and services required to support intensive care unit survivors on their journey to recovery.

Delayed gastric emptying, that manifests clinically as intolerance to enteral feeding, occurs in over 50% of critically ill patients and has a major impact on patient morbidity and mortality. Despite the recognition that the proximal stomach has a major role in gastric emptying of liquids, only the motor activity of the antro-pyloro-duodenal region has been evaluated in detail. In addition, many of the proposed risk factors for the gastric dysmotility, particularly a prior history of diabetes mellitus, have not been evaluated formally but have been extrapolated from data from non-critically ill patients. The currently available prokinetic drugs, erythromycin and metoclopramide, are considered to be the first line treatment for feed intolerance. However, neither data comparing the effectiveness of these agents nor the data on the effects of combination of therapy in the treatment of feed intolerance are available. The aims of this thesis were, therefore, to examine: (i) proximal gastric motor activity and the association between proximal and distal motility; (ii) the relationship between entero-gastric humoral responses to nutrients, gastric emptying and feed intolerance; (iii) the impact of admission diagnoses, choice of sedations, timing of initiation of feeding, and pre-existing history of diabetes mellitus on gastric emptying and feed intolerance; and (iv) the efficacy of erythromycin, metoclopramide and combination of these drugs in treatment of feed intolerance in critically ill patients. The current thesis indicates that motor activity is impaired in multiple regions of the stomach in the critically ill. When compared to healthy humans, proximal gastric relaxation was prolonged and fundic wave activity was educed during small intestinal nutrient infusion in critically ill patients. In addition, simultaneous assessment of proximal and distal gastric motility demonstrated a possible disruption of the motor integration between the proximal and distal stomach. In light of the recent data that suggested a significantly greater proportion of meal distributed proximally in critically ill patients with delayed gastric emptying (Nguyen, et al. 2006), the disruption of the gastric motor integration and the prolonged gastric relaxation in response to duodenal nutrients may play a significant role in the pathogenesis of slow gastric emptying during critical illness, especially as liquid formulae. The entero-gastric hormonal feedback responses were also disturbed during critical illness. Both fasting and duodenal nutrient-stimulated plasma CCK and PYY concentrations were significantly higher in critically ill patients, particularly those who did not tolerated gastric feeds. The rate of gastric emptying of a liquid meal was inversely related to both fasting and postprandial plasma CCK and PYY concentrations, supporting the potential role of plasma CCK and PYY in the pathogenesis of gastric dysmotility in critically ill patients. Admission diagnosis, choice of sedative drug and blood glucose control but not the timing of enteral feeds were important factors for delayed gastric emptying and feed intolerance in these patients. In particular, delaying enteral feeding by 4 days had no impact on the rate of gastric emptying, intra-gastric meal distribution, or plasma CCK and PYY concentrations. Contrary to traditional belief, critically ill patients with a pre-existing diagnosis of type 2 DM have only a minor disturbance to the proximal stomach, a relatively normal gastric emptying and are at no higher risk of feed intolerance than those without DM, suggesting the presence of pre-existing DM 2 in critically ill patients should not influence the standard practice of gastric feeding. Therapeutically, short-term treatment with low dose erythromycin was more effective than metoclopramide, but the effectiveness decreased rapidly overtime at similar rate as observed with metoclopramide. In patients who failed to response to either agent, treatment with both agents was highly effective in re-establishing feeding success. The use of combination therapy as the initial treatment for feed intolerance was also more effective than erythromycin alone and had less tachyphylaxis. Treatment with erythromycin and metoclopramide, either as a single agent or in combination did not associated with major cardiovascular adverse side effects. Although diarrhoea was a common side effect and was highest with combination therapy, it was not associated with Clostridium difficile infection and settled quickly after the cessation of the prokinetic therapy. In summary, the work performed in the current thesis has provided substantial insights into the understanding of the nature, risk factors, pathogenesis and treatment of disturbed gastric motor function in critically ill patients. Not only do these findings stimulate further research into the mechanisms responsible for gastric dysmotility in critical illness, they also lead to the development of new strategies for optimizing the management of feed intolerance. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1320667 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Until recently, long-term effects of a critical illness (CI) have received little attention from intensive care staff, who have traditionally measured outcome from an intensive care unit (ICU) by morbidity and mortality. However, it is now acknowledged that CI is a continuum that begins before ICU and continues to impact on a patient�s quality of life after they have been discharged home. Measuring health related quality of life (HRQOL) is a complex matter due to its multifaceted, subjective and dynamic nature. There has been a lack of consensus in the literature regarding the most appropriate methodological approaches and measuring instruments to use. This disparity has impeded comparison between studies. The aim of this thesis was to review the literature between January 1998 and December 2003 that focused on HRQOL for patients after a CI to identify and summarise themes and key outcomes. There were two main areas of focus - the methods used to measure the effects of the CI, and evaluation of the patient outcomes. An electronic search for relevant articles was conducted using the common clinical research databases and key words such as health related quality of life, outcomes and critical illness. Reference lists from these articles and conference proceedings were reviewed to identify further studies. There were 74 primary papers identified that reflected a number of subcategories including general ICU, Acute Respiratory Distress Syndrome (ARDS), and elderly patients. There were four categories of instruments used in the literature including those that measured acuity of illness, physical functioning, psychological functioning and HRQOL. The majority of studies used more than one measuring instrument, most of which had been previously validated. Results from the studies were diverse, but it is apparent that physical and psychological recovery from a CI may be a slow and varied process. Most studies were observational; only one randomised control study examined the benefits of a physical exercise program for patients post-hospital discharge. In general, there was no evidence of how to translate the study findings into some form of structured program to assist the patient with any identified problems. To enhance continuum of care, integration of ICU, hospital and rehabilitation services could target identified physical and psychological problems to assist patient recovery. However, strong evidence on the benefits of initiatives such as inpatient follow-up, outpatient clinics and use of ICU diaries is yet to be demonstrated.

Delayed gastric emptying, that manifests clinically as intolerance to enteral feeding, occurs in over 50% of critically ill patients and has a major impact on patient morbidity and mortality. Despite the recognition that the proximal stomach has a major role in gastric emptying of liquids, only the motor activity of the antro-pyloro-duodenal region has been evaluated in detail. In addition, many of the proposed risk factors for the gastric dysmotility, particularly a prior history of diabetes mellitus, have not been evaluated formally but have been extrapolated from data from non-critically ill patients. The currently available prokinetic drugs, erythromycin and metoclopramide, are considered to be the first line treatment for feed intolerance. However, neither data comparing the effectiveness of these agents nor the data on the effects of combination of therapy in the treatment of feed intolerance are available. The aims of this thesis were, therefore, to examine: (i) proximal gastric motor activity and the association between proximal and distal motility; (ii) the relationship between entero-gastric humoral responses to nutrients, gastric emptying and feed intolerance; (iii) the impact of admission diagnoses, choice of sedations, timing of initiation of feeding, and pre-existing history of diabetes mellitus on gastric emptying and feed intolerance; and (iv) the efficacy of erythromycin, metoclopramide and combination of these drugs in treatment of feed intolerance in critically ill patients. The current thesis indicates that motor activity is impaired in multiple regions of the stomach in the critically ill. When compared to healthy humans, proximal gastric relaxation was prolonged and fundic wave activity was educed during small intestinal nutrient infusion in critically ill patients. In addition, simultaneous assessment of proximal and distal gastric motility demonstrated a possible disruption of the motor integration between the proximal and distal stomach. In light of the recent data that suggested a significantly greater proportion of meal distributed proximally in critically ill patients with delayed gastric emptying (Nguyen, et al. 2006), the disruption of the gastric motor integration and the prolonged gastric relaxation in response to duodenal nutrients may play a significant role in the pathogenesis of slow gastric emptying during critical illness, especially as liquid formulae. The entero-gastric hormonal feedback responses were also disturbed during critical illness. Both fasting and duodenal nutrient-stimulated plasma CCK and PYY concentrations were significantly higher in critically ill patients, particularly those who did not tolerated gastric feeds. The rate of gastric emptying of a liquid meal was inversely related to both fasting and postprandial plasma CCK and PYY concentrations, supporting the potential role of plasma CCK and PYY in the pathogenesis of gastric dysmotility in critically ill patients. Admission diagnosis, choice of sedative drug and blood glucose control but not the timing of enteral feeds were important factors for delayed gastric emptying and feed intolerance in these patients. In particular, delaying enteral feeding by 4 days had no impact on the rate of gastric emptying, intra-gastric meal distribution, or plasma CCK and PYY concentrations. Contrary to traditional belief, critically ill patients with a pre-existing diagnosis of type 2 DM have only a minor disturbance to the proximal stomach, a relatively normal gastric emptying and are at no higher risk of feed intolerance than those without DM, suggesting the presence of pre-existing DM 2 in critically ill patients should not influence the standard practice of gastric feeding. Therapeutically, short-term treatment with low dose erythromycin was more effective than metoclopramide, but the effectiveness decreased rapidly overtime at similar rate as observed with metoclopramide. In patients who failed to response to either agent, treatment with both agents was highly effective in re-establishing feeding success. The use of combination therapy as the initial treatment for feed intolerance was also more effective than erythromycin alone and had less tachyphylaxis. Treatment with erythromycin and metoclopramide, either as a single agent or in combination did not associated with major cardiovascular adverse side effects. Although diarrhoea was a common side effect and was highest with combination therapy, it was not associated with Clostridium difficile infection and settled quickly after the cessation of the prokinetic therapy. In summary, the work performed in the current thesis has provided substantial insights into the understanding of the nature, risk factors, pathogenesis and treatment of disturbed gastric motor function in critically ill patients. Not only do these findings stimulate further research into the mechanisms responsible for gastric dysmotility in critical illness, they also lead to the development of new strategies for optimizing the management of feed intolerance. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1320667 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008